International Agency for Research on Cancer (IARC) - Summaries & Evaluations

GENERAL CONCLUSIONS ON HORMONES

VOL.: 6 (1974) (p. 235)

Steroid hormones have an essential role in the growth, differentiation
and function of many tissues in both animals and man. It is established
by animal experimentation that modification of the hormonal environment
by gonadectomy, by pregnancy or by exogenous administration of
steroids can greatly increase or decrease the spontaneous occurrence
of tumours or the induction of tumours by applied carcinogenic
agents. In man also, there is evidence that differences in endogenous
hormone levels may be associated with differences in tumour incidence.
It is possible, therefore, that the incidence of human tumours
could be increased or decreased by a specific mode of exogenous
hormone administration, but this cannot be predicted.

For an administered oestrogen seriously to perturb the hormonal
environment of man, the intake must be of the same order as, or
greater than, the amounts of oestrogens produced endogenously.
The intake of steroids for effective contraceptive medication
has to be sufficient to disturb the hormonal environment, and
in fact such a disturbance is a requisite of fertility inhibition.
The possibility that a carcinogenic risk may be involved in such
medication must therefore be considered. For example, the minimum
effective dose of diethylstilboestrol of 6 mg/kg bw/day
for mammary carcinogenesis in mice is of the same order as the
doses used for therapy in women (0.5-5 mg/day). At the same time,
it should be remembered in regard to both oestrogens and progestins
in contraceptive medication that the steroid hormones of pregnancy
have actions similar to those of the contraceptive agents.

Animal data

Administration of the natural oestrogens, oestradiol-17b and
oestrone, increases the incidence of tumours in a number of organs
in a variety of animal species. Data on the synthetic oestrogen
diethylstilboestrol indicate that this compound has a carcinogenic
potential comparable with those of oestradiol-17b and of oestrone,
and there is no evidence to suggest that its carcinogenic properties
are due to some special biological function other than its oestrogenic
activity, which is of the same order as that of oestradiol-17b.
The other synthetic oestrogens, ethinyloestradiol and mestranol,
have been shown to be carcinogenic in a limited number of animal
studies, but there is no reason to suppose that they are more
or less carcinogenic than are other oestrogens at comparable levels
of oestrogenic activity. Because of lack of experimental data
no attempt has been made to show a relationship between carcinogenic
potential and oestrogenic activity for any of the compounds considered.

The majority of experimental animal treatments with oestrogens,
which have resulted in carcinogenesis, have been at very high
dose levels. There is inadequate information at present, however,
to indicate the minimum dose requirements, and these could be
much lower than those commonly employed in animal studies.

In the case of the natural progestin, progesterone, there is not
much evidence that it has a carcinogenic potential per se.
There is, however, evidence that low doses of progesterone administered
over long periods act in combination with carcinogenic agents
such as some viruses or chemicals. In part, therefore, the hazard
of long-term administration of synthetic progestins is comparable
with that associated with progesterone in increasing the incidence
of tumours due to other agents. This is dependent on the degree
of progestational activity possessed by the compound in question
relative to its other hormonal characteristics.

The synthetic progestins, such as norethynodrel and norethisterone,
have some carcinogenic potential in animal systems even when administered
alone. This is increased by combination with oestrogens. The progesterone
analogue, chlormadinone acetate, has not demonstrated carcinogenic
properties when given alone to rodents. When combined with oestrogens,
its carcinogenic potential appears to parallel that of the oestrogenic
component. Evidence for its tumour-inducing capacity in the canine
breast does not seem to be sufficient evidence, alone, for the
prohibition of its use in women.

There is no evidence at present to suggest that steroid hormones
are ultimate carcinogens; on the contrary, all the evidence suggests
that they act, in part at least, by modification of pituitary
hormone secretion in which prolactin is a factor. In general,
it appears that steroids increase the probability of tumour occurrence
in those tissues normally responsive to stimulation by such steroids.

Human data

Steroid hormones, such as those considered in this monograph,
have been and are used extensively in human therapy. When they
are used for the treatment of disseminated cancer such as that
of the breast, prostate and endometrium, their effect on tumour
growth and the severity of side-effects are the major considerations.
In the use of steroid therapy for less vital reasons (for example,
menstrual disorders, menopausal syndrome, pregnancy maintenance,
osteoporosis, protein anabolism, gonadal deficiency), however,
the question of carcinogenic hazard becomes more pertinent. With
the continuing development of steroid use for the control of conception,
the question of possible carcinogenic hazards has become of major
importance.

As stated in the general introduction, "at the present time
no attempt can be made to interpret the animal data directly in
terms of human risk since no objective criteria are available
to do so". There is, therefore, no substitute for direct
observation in the human being, although the animal experimentation
provides important clues as to where one should look for human
risks. Epidemiological studies to explore the possibility of a
carcinogenic effect of administered oestrogens and progestins
in man, however, suffer from two major difficulties. Firstly,
the interval between the commencement of administration and the
possible appearance of cancer is likely to be long. Secondly,
to detect a small or moderate change in risk, observations on
very large numbers of subjects are required.

With these reservations in mind the following can be said:

1. Diethylstilboestrol

(a) The administration of this drug to women during pregnancy
is associated with an increased risk of vaginal or cervical adenocarcinoma
in their exposed female offspring.

(b) There may also be an increased risk of endometrial
carcinoma in women with gonadal dysgenesis treated with this drug.

(c) It is possible that the administration of the drug
therapeutically to men with carcinoma of the prostate increases
the risk of cancer of the breast.

2. Other oestrogens

The administration of oestrogens for treatment of the menopausal
syndrome and related conditions has not been shown to be associated
with a risk of cancer.

3. Oral contraceptives

The administration of these preparations has not as yet been shown
to alter the risk of cancer of the breast. The evidence with respect
to cancer of the cervix is somewhat less consistent.